Interleukin-12 (IL-12) is a heterodimeric cytokine (p70) which plays a key role in immune responses by bridging innate resistance and antigen-specific adaptive immunity. Trinchieri (1993) Immunol Today 14: 335. For example, it promotes type 1 T helper cell (Th1) responses and, hence, cell-mediated immunity. (See Chan et al. (1991) J Exp Med 173: 869; Seder et al. (1993) Proc Natl Acad Sci USA 90: 10188; Manetti et al. (1993) J Exp Med 177: 1199; and Hsieh et al. (1993) Science 260: 547, the entire teachings of each of these references are incorporated here in by reference). IL-12 is composed of two, disulfide linked, independently regulated subunits, p35 and p40. IL-12 is produced by phagocytic cells and antigen presenting cells, in particular, macrophages and dendritic cells, upon stimulation with bacteria, bacterial products such as lipopolysaccharide (LPS), and intracellular parasites. The well-documented biological functions of IL-12 are induction of interferon-γ (INF-γ) expression from T and NK cells and differentiation of naïve T cells toward the Th1 T lymphocyte type. IFN-γ, expression of which is induced by IL-12, is a strong and selective enhancer of IL-12 production from monocytes and macrophages.
The cytokine IL-23 is a heterodimer composed of a p19 subunit and the same p40 subunit as IL-12. Exposure of activated CD4+ T cells to IL-23 causes them to develop into a novel T cell subset (ThIL-17 cells) characterized by the production of IL-17 (Langrish, et al., Immunological Reviews (2004), 202:96-105, the entire teachings of which are incorporated herein by reference). IL-17 has been implicated in a number of autoimmune diseases. For example, IL-23 knock out mice have a severely impaired IL-17 response and are resistant to experimental autoimmune encephalitis (EAE) (a model for multiple sclerosis) and collagen-induced arthritis. In addition, IL-17 has been shown to increase neutrophil activity in the lungs of patients with acute and chronic asthma and in patients with chronic obstructive pulmonary disease (COPD).
IL-27 is formed by the association of EBI3, a polypeptide related to the p40 subunit of IL-12, and p28, a protein related to the p35 subunit of IL-12. IL-27 promotes the growth of T cells and, like IL-12, is thought to play a role in the differentiation of naïve T cells to Th1 cells. Pflanz et al., Immunity (2002), 16:779-790.
It has been suggested that, particularly in chronic diseases in which there is ongoing production of IFN-γ, IL-12 production is augmented by IFN-γ. It is presumed that after an infective or inflammatory stimulus that provokes IL-12 production, the powerful feedback loop promotes IL-12-induced IFN-γ to further augment IL-12 production, leading to consequent excessive production of pro-inflammatory cytokines. In particular, activated CD4+ T cells produced by this process when exposed to IL-23 differentiate into a subset of T cells that produce the pro-inflammatory cytokine, IL-17. Furthermore, it has been suggested that IL-27 induces the expression of T-bet, a major Th1-specific transcription factor, and its downstream target IL-12R β2, independently of IFN-γ. In addition, IL-27 suppresses the expression of GATA-3. GATA-3 inhibits Th1 development and causes loss of IL-12 signaling through suppression of IL-12R β2 and Stat4 expression. Lucas et al., PNAS (2003), 100:15047-15052.
IL-12, IL-23 and IL-27, as well as IL-17, play a critical role in many autoimmune diseases including, but not limited to, multiple sclerosis, sepsis, myasthenia gravis, autoimmune neuropathies, Guillain-Barré syndrome, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides, Wegener's granulomatosis, Behcet's disease, psoriasis, psoriatic arthritis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, ulcerative colitis, interstitial pulmonary fibrosis, myelofibrosis, hepatic fibrosis, myocarditis, thyroditis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 or immune-mediated diabetes mellitus, Grave's disease, Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, autoimmune disease of the adrenal gland; rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies, ankylosing spondylitis, Sjogren's syndrome and graft-versus-host disease. (See, for example, Gately et al. (1998) Annu Rev Immunol. 16: 495; and Abbas et al. (1996) Nature 383: 787, the entire teachings of which are incorporated by reference.)
Inhibiting IL-12, IL-23 and IL-27 is an approach to treating autoimmune and inflammatory disorders by inhibiting the production of Th1 and ThIL-17 cells and thereby down-regulating pro-inflammatory cytokines such as IL-17. (Trembleau et al. (1995) Immunol. Today 16: 383; and Adorini et al. (1997) Chem. Immunol. 68: 175; and Langrish, et al., Immunological Reviews (2004), 202:96-105, the entire teachings of both of these articles are incorporated herein by reference). Therefore, compounds that inhibit the production of IL-12, IL-23 and IL-27 are useful for treating autoimmune and inflammatory disorders.